ISSN (print) 1997-6933     ISSN (online) 2500-2139
Том 16 № 3 (2023), ОБЗОРЫ
Том 16 № 3 (2023)
ОБЗОРЫ

Классическая лимфома Ходжкина: структура опухоли и прогностическое значение иммунного микроокружения

Опубликовано 20.02.2024
Артем Александрович Гусак
НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022
К.В. Лепик
НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022
Л.В. Федорова
НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022
В.В. Маркелов
НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022
В.В. Байков
НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022
2023-3
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Ключевые слова

классическая лимфома Ходжкина
микроокружение
иммунные контрольные точки
поляризация макрофагов
иммуносупрессивная ниша

Как цитировать

Гусак А.А., Лепик К.В., Федорова Л.В., Маркелов В.В., Байков В.В. Классическая лимфома Ходжкина: структура опухоли и прогностическое значение иммунного микроокружения. Клиническая онкогематология. 2024;(3):242–262. doi:10.21320/2500-2139-2023-16-3-242-262.
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Аннотация

Классическая лимфома Ходжкина (ЛХ) представляет собой уникальное злокачественное новообразование лимфатической системы, характеризующееся наличием опухолевых клеток (Ходжкина и Рид—Штернберга) в воспалительном и иммуносупрессивном микроокружении. Микроокружение ЛХ — комплексная динамичная среда, включающая иммунные клетки, стромальные элементы и компоненты внеклеточного матрикса, которые взаимодействуют друг с другом и с опухолевыми клетками. От характера этих взаимодействий во многом зависит как прогрессирование заболевания, так и ответ на терапию. В настоящее время возрастает интерес к изучению структуры и функции микроокружения ЛХ, его прогностического значения, потенциала его компонентов в качестве новых мишеней для лекарственной терапии. В последнее десятилетие значительно улучшились результаты лечения рефрактерных форм ЛХ, в частности, за счет применения ингибиторов PD-1 ниволумаба и пембролизумаба. Высокая чувствительность ЛХ к анти-PD-1-терапии обусловлена формированием PD-1/PD-L1-ассоциированной ниши в ткани опухоли. Основой ниши является интенсивная экспрессия PD-L1 опухолевыми клетками, макрофагами и экспрессия его рецептора PD-1 Т-клетками и М2-макрофагами. Накапливается все больше сведений о возможных механизмах противоопухолевого ответа у пациентов с ЛХ при анти-PD-1-терапии, противоречащих концепции классического CD8-опосредованного ответа при солидных опухолях. Вероятно, цитотоксические эффекты анти-PD-1-терапии в ткани ЛХ достигаются путем взаимодействия между опухолевыми клетками, макрофагами и CD4-позитивными Т-лимфоцитами. В обзоре представлены сведения о структурных и регуляторных взаимоотношениях опухолевых клеток и элементов микроокружения, описываются новые терапевтические подходы, основанные на использовании в качестве мишеней различных компонентов опухолевого микроокружения, суммированы имеющиеся к настоящему времени данные о возможности прогнозирования на основе изучения характеристик микроокружения ЛХ.

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Библиографические ссылки

  1. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14(8):517–34. doi: 10.1038/nrc3774.
  2. Gallaher JA, Brown JS, Anderson ARA. The impact of proliferation-migration trade-offs on phenotypic evolution in cancer. Sci Rep. 2019;9(1):2425. doi: 10.1038/s41598-019-39636-x.
  3. Kuppers R, Engert A, Hansmann ML. Hodgkin lymphoma. J Clin Invest. 2012;122(10):3439–47. doi: 10.1172/JCI61245.
  4. Hertel CB, Zhou XG, Hamilton-Dutoit SJ, Junker S. Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma. Oncogene. 2002;21(32):4908–20. doi: 10.1038/sj.onc.1205629.
  5. Kuppers R, Rajewsky K. The origin of Hodgkin and Reed/Sternberg cells in Hodgkin’s disease. Annu Rev Immunol. 1998;16:471–93. doi: 10.1146/annurev.immunol.16.1.471.
  6. Schwering I, Brauninger A, Klein U, et al. Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2003;101(4):1505–12. doi: 10.1182/blood-2002-03-0839.
  7. Weniger MA, Kuppers R. NF-κB deregulation in Hodgkin lymphoma. Semin Cancer Biol. 2016;39:32–9. doi: 10.1016/j.semcancer.2016.05.001.
  8. Tiacci E, Ladewig E, Schiavoni G, et al. Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood. 2018;131(22):2454–65. doi: 10.1182/blood-2017-11-814913.
  9. Garces de Los Fayos Alonso I, Liang HC, Turner SD, et al. The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas. Cancers (Basel). 2018;10(4):93. doi: 10.3390/cancers10040093.
  10. Jundt F, Anagnostopoulos I, Forster R, et al. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002;99(9):3398–403. doi: 10.1182/blood.v99.9.3398.
  11. Zheng B, Fiumara P, Li YV, et al. MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. Blood. 2003;102(3):1019–27. doi: 10.1182/blood-2002-11-3507.
  12. Aravinth SP, Rajendran S, Li Y, et al. Epstein-Barr virus-encoded LMP1 induces ectopic CD137 expression on Hodgkin and Reed-Sternberg cells via the PI3K-AKT-mTOR pathway. Leuk Lymphoma. 2019;60(11):2697–704. doi: 10.1080/10428194.2019.1607330.
  13. Tiacci E, Doring C, Brune V, et al. Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood. 2012;120(23):4609–20. doi: 10.1182/blood-2012-05-428896.
  14. Gruss HJ, Hirschstein D, Wright B, et al. Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin’s disease. Blood. 1994;84(7):2305–14.
  15. Gruss HJ, Duyster J, Herrmann F. Structural and biological features of the TNF receptor and TNF ligand superfamilies: interactive signals in the pathobiology of Hodgkin’s disease. Ann Oncol. 1996;7(Suppl 4):19–26. doi: 10.1093/annonc/7.suppl_4.s19.
  16. Yurchenko M, Sidorenko SP. Hodgkin’s lymphoma: the role of cell surface receptors in regulation of tumor cell fate. Exp Oncol. 2010;32(4):214–23.
  17. Chiu A, Xu W, He B, et al. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL. Blood. 2007;109(2):729–39. doi: 10.1182/blood-2006-04-015958.
  18. Brune MM, Juskevicius D, Haslbauer J, et al. Genomic Landscape of Hodgkin Lymphoma. Cancers (Basel). 2021;13(4):682. doi: 10.3390/cancers13040682.
  19. Steidl C, Telenius A, Shah SP, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood. 2010;116(3):418–27. doi: 10.1182/blood-2009-12-257345.
  20. Thomas RK, Kallenborn A, Wickenhauser C, et al. expression of c-FLIP in Hodgkin and Reed-Sternberg cells. Am J Pathol. 2002;160(4):1521–8. doi: 10.1016/S0002-9440(10)62578-3.
  21. Zhao X, Qiu W, Kung J, et al. Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008;32(2):275–85. doi: 10.1016/j.leukres.2007.05.024.
  22. Maggio EM, Van Den Berg A, de Jong D, et al. Low frequency of FAS mutations in Reed-Sternberg cells of Hodgkin’s lymphoma. Am J Pathol. 2003;162(1):29–35. doi: 10.1016/S0002-9440(10)63795-9.
  23. Metkar SS, Naresh KN, Redkar AA, et al. Expression of Fas and Fas ligand in Hodgkin’s disease. Leuk Lymphoma. 1999;33(5–6):521–30. doi: 10.3109/10428199909058456.
  24. Verbeke CS, Wenthe U, Grobholz R, Zentgraf H. Fas ligand expression in Hodgkin lymphoma. Am J Surg Pathol. 2001;25(3):388–94. doi: 10.1097/00000478-200103000-00014.
  25. Mathas S, Lietz A, Anagnostopoulos I, et al. c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis. J Exp Med. 2004;199(8):1041–52. doi: 10.1084/jem.20031080.
  26. Weniger MA, Kuppers R. Molecular biology of Hodgkin lymphoma. Leukemia. 2021;35(4):968–81. doi: 10.1038/s41375-021-01204-6.
  27. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol. 2016;34(23):2690–7. doi: 10.1200/JCO.2016.66.4482.
  28. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond. Adv Exp Med Biol. 2020;1248:33–59. doi: 10.1007/978-981-15-3266-5_3.
  29. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77. doi: 10.1182/blood-2010-05-282780.
  30. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):1611–8. doi: 10.1158/1078-0432.CCR-11-1942.
  31. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011;471(7338):377–81. doi: 10.1038/nature09754.
  32. Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood. 2015;125(7):1061–72. doi: 10.1182/blood-2014-11-610436.
  33. Dhatchinamoorthy K, Colbert JD, Rock KL. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Front Immunol. 2021;12:636568. doi: 10.3389/fimmu.2021.636568.
  34. Thibodeau J, Bourgeois-Daigneault MC, Lapointe R. Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology. 2012;1(6):908–16. doi: 10.4161/onci.21205.
  35. Roemer MG, Advani RH, Redd RA, et al. Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status. Cancer Immunol Res. 2016;4(11):910–6. doi: 10.1158/2326-6066.CIR-16-0201.
  36. Roemer MGM, Redd RA, Cader FZ, et al. Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma. J Clin Oncol. 2018;36(10):942–50. doi: 10.1200/JCO.2017.77.3994.
  37. Murray P, Bell A. Contribution of the Epstein-Barr Virus to the Pathogenesis of Hodgkin Lymphoma. Curr Top Microbiol Immunol. 2015;390(Pt 1):287–313. doi: 10.1007/978-3-319-22822-8_12.
  38. Xu M, Zhang WL, Zhu Q, et al. Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies. Theranostics. 2019;9(4):1115–24. doi: 10.7150/thno.29622.
  39. Massini G, Siemer D, Hohaus S. EBV in Hodgkin Lymphoma. Mediterr J Hematol Infect Dis. 2009;1(2):e2009013. doi: 10.4084/MJHID.2009.013.
  40. Murray PG, Young LS. An etiological role for the Epstein-Barr virus in the pathogenesis of classical Hodgkin lymphoma. Blood. 2019;134(7):591–6. doi: 10.1182/blood.2019000568.
  41. Carbone A, Gloghini A. Epstein Barr Virus-Associated Hodgkin Lymphoma. Cancers (Basel). 2018;10(6):163. doi: 10.3390/cancers10060163.
  42. Santisteban-Espejo A, Perez-Requena J, Atienza-Cuevas L, et al. Prognostic Role of the Expression of Latent-Membrane Protein 1 of Epstein-Barr Virus in Classical Hodgkin Lymphoma. Viruses. 2021;13(12):2523. doi: 10.3390/v13122523.
  43. Kuppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9(1):15–27. doi: 10.1038/nrc2542.
  44. Rengstl B, Newrzela S, Heinrich T, et al. Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells. Proc Natl Acad Sci USA. 2013;110(51):20729–34. doi: 10.1073/pnas.1312509110.
  45. Aldinucci D, Gloghini A, Pinto A, et al. The classical Hodgkin’s lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol. 2010;221(3):248–63. doi: 10.1002/path.2711.
  46. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720–48. doi: 10.1038/s41375-022-01620-2.
  47. Bennett MH, Tu A, Hudson GV. Analysis of grade 1 Hodgkin’s disease (Report no 6). Clin Radiol. 1981;32(5):491–8. doi: 10.1016/s0009-9260(81)80174-2.
  48. Bennett MH, MacLennan KA, Easterling MJ, et al. The prognostic significance of cellular subtypes in nodular sclerosing Hodgkin’s disease: an analysis of 271 non-laparotomised cases (BNLI report no. 22). Clin Radiol. 1983;34(5):497–501. doi: 10.1016/s0009-9260(83)80148-2.
  49. MacLennan KA, Bennett MH, Tu A, et al. Relationship of histopathologic features to survival and relapse in nodular sclerosing Hodgkin’s disease. A study of 1659 patients. Cancer. 1989;64(8):1686–93. doi: 10.1002/1097-0142(19891015)64:8<1686::aid-cncr2820640822>3.0.co;2-i.
  50. Van Spronsen DJ, Vrints LW, Hofstra G, et al. Disappearance of prognostic significance of histopathological grading of nodular sclerosing Hodgkin’s disease for unselected patients, 1972–92. Br J Haematol. 1997;96(2):322–7. doi: 10.1046/j.1365-2141.1997.d01-2010.x.
  51. Pileri SA, Ascani S, Leoncini L, et al. Hodgkin’s lymphoma: the pathologist’s viewpoint. J Clin Pathol. 2002;55(3):162–76. doi: 10.1136/jcp.55.3.162.
  52. Lorenzen J, Thiele J, Fischer R. The mummified Hodgkin cell: cell death in Hodgkin’s disease. J Pathol. 1997;182(3):288–98. doi: 10.1002/(SICI)1096-9896(199707)182:3<288::AID-PATH859>3.0.CO;2-3.
  53. Eberle FC, Mani H, Jaffe ES. Histopathology of Hodgkin’s lymphoma. Cancer J. 2009;15(2):129–37. doi: 10.1097/PPO.0b013e31819e31cf.
  54. Wang HW, Balakrishna JP, Pittaluga S, Jaffe ES. Diagnosis of Hodgkin lymphoma in the modern era. Br J Haematol. 2019;184(1):45–59. doi: 10.1111/bjh.15614.
  55. Tzankov A, Bourgau C, Kaiser A, et al. Rare expression of T-cell markers in classical Hodgkin’s lymphoma. Mod Pathol. 2005;18(12):1542–9. doi: 10.1038/modpathol.3800473.
  56. Venkataraman G, Song JY, Tzankov A, et al. Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival. Blood. 2013;121(10):1795–804. doi: 10.1182/blood-2012-06-439455.
  57. Wang M, Zhao J, Zhang L, et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017;8(5):761–73. doi: 10.7150/jca.17648.
  58. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118(1):9–16. doi: 10.1038/bjc.2017.434.
  59. Andre MPE, Carde P, Viviani S, et al. Long-term overall survival and toxicities of ABVD vs BEACOPP in advanced Hodgkin lymphoma: A pooled analysis of four randomized trials. Cancer Med. 2020;9(18):6565–75. doi: 10.1002/cam4.3298.
  60. Engert A, Diehl V, Franklin J, et al. Escalated-Dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009;27(27):4548–54. doi: 10.1200/JCO.2008.19.8820.
  61. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: A randomised trial. Lancet. 2002;359(9323):2065–71. doi: 10.1016/S0140-6736(02)08938-9.
  62. Arai S, Fanale M, Devos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma. 2013;54(11):2531–3. doi: 10.3109/10428194.2013.798868.
  63. Chen R, Gopal A, Smith SE, et al. Five-Year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016;128(12):1562–6. doi: 10.1182/blood-2016-02-699850.
  64. Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: Extended follow-up of the multicohort single-arm phase II checkmate 205 trial. J Clin Oncol. 2018;36(14):1428–39. doi: 10.1200/JCO.2017.76.0793.
  65. Lepik KV, Mikhailova NB, Moiseev IS, et al. Nivolumab for the treatment of relapsed and refractory classical Hodgkin lymphoma after ASCT and in ASCT-naive patients. Leuk Lymphoma. 2019;60(9):2316–9. doi: 10.1080/10428194.2019.1573368.
  66. Flores MBA, Corvinos MSa, Elez MM, et al. A new approach to the study of Hodgkin lymphoma by flow cytometry. Pathology. 2023;55(1):86–93. doi: 10.1016/j.pathol.2022.07.005.
  67. Cader FZ, Schackmann RCJ, Hu X, et al. Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment. Blood. 2018;132(8):825–36. doi: 10.1182/blood-2018-04-843714.
  68. Scott DW, Steidl C. The classical Hodgkin lymphoma tumor microenvironment: macrophages and gene expression-based modeling. Hematology Am Soc Hematol Educ Program. 2014;2014(1):144–50. doi: 10.1182/asheducation-2014.1.144.
  69. Carey CD, Gusenleitner D, Lipschitz M, et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017;130(22):2420–30. doi: 10.1182/blood-2017-03-770719.
  70. Elaldi R, Hemon P, Petti L, et al. High Dimensional Imaging Mass Cytometry Panel to Visualize the Tumor Immune Microenvironment Contexture. Front Immunol. 2021;12:666233. doi: 10.3389/fimmu.2021.666233.
  71. Ptacek J, Locke D, Finck R, et al. Multiplexed ion beam imaging (MIBI) for characterization of the tumor microenvironment across tumor types. Lab Invest. 2020;100(8):1111–23. doi: 10.1038/s41374-020-0417-4.
  72. Aldinucci D, Celegato M, Casagrande N. Microenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance. Cancer Lett. 2016;380(1):243–52. doi: 10.1016/j.canlet.2015.10.007.
  73. Aldinucci D, Lorenzon D, Cattaruzza L, et al. Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions. Int J Cancer. 2008;122(4):769–76. doi: 10.1002/ijc.23119.
  74. Van den Berg A, Visser L, Poppema S. High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltrate in Hodgkin’s lymphoma. Am J Pathol. 1999;154(6):1685–91. doi: 10.1016/S0002-9440(10)65424-7.
  75. Hnatkova M, Mocikova H, Trneny M, Zivny J. The biological environment of Hodgkin’s lymphoma and the role of the chemokine CCL17/TARC. Prague Med Rep. 2009;110(1):35–41.
  76. Niens M, Visser L, Nolte IM, et al. Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22. Br J Haematol. 2008;140(5):527–36. doi: 10.1111/j.1365-2141.2007.06964.x.
  77. Cattaruzza L, Gloghini A, Olivo K, et al. Functional coexpression of interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: Involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin’s lymphoma. Int J Cancer. 2009;125(5):1092–101. doi: 10.1002/ijc.24389.
  78. Vera-Lozada G, Minnicelli C, Segges P, et al. Interleukin 10 (IL-10) proximal promoter polymorphisms beyond clinical response in classical Hodgkin lymphoma: Exploring the basis for the genetic control of the tumor microenvironment. Oncoimmunology. 2018;7(5):e1389821. doi: 10.1080/2162402X.2017.1389821.
  79. Hsu SM, Lin J, Xie SS, et al. Abundant expression of transforming growth factor-beta 1 and -beta 2 by Hodgkin’s Reed-Sternberg cells and by reactive T lymphocytes in Hodgkin’s disease. Hum Pathol. 1993;24(3):249–55. doi: 10.1016/0046-8177(93)90034-e.
  80. Kadin ME, Agnarsson BA, Ellingsworth LR, Newcom SR. Immunohistochemical evidence of a role for transforming growth factor beta in the pathogenesis of nodular sclerosing Hodgkin’s disease. Am J Pathol. 1990;136(6):1209–14.
  81. Maggio E, van den Berg A, Diepstra A, et al. Chemokines, cytokines and their receptors in Hodgkin’s lymphoma cell lines and tissues. Ann Oncol. 2002;13(Suppl 1):52–6. doi: 10.1093/annonc/13.s1.52.
  82. Fischer M, Juremalm M, Olsson N, et al. Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue. Int J Cancer. 2003;107(2):197–201. doi: 10.1002/ijc.11370.
  83. Liu Y, Sattarzadeh A, Diepstra A, et al. The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component. Semin Cancer Biol. 2014;24:15–22. doi: 10.1016/j.semcancer.2013.07.002.
  84. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood. 2002;99(12):4283–97. doi: 10.1182/blood-2002-01-0099.
  85. Machado L, Jarrett R, Morgan S, et al. Expression and function of T cell homing molecules in Hodgkin’s lymphoma. Cancer Immunol Immunother. 2009;58(1):85–94. doi: 10.1007/s00262-008-0528-z.
  86. Opinto G, Agostinelli C, Ciavarella S, et al. Hodgkin Lymphoma: A Special Microenvironment. J Clin Med. 2021;10(20):4665. doi: 10.3390/jcm10204665.
  87. Zijtregtop EAM, Tromp I, Dandis R, et al. The Prognostic Value of Eight Immunohistochemical Markers Expressed in the Tumor Microenvironment and on Hodgkin Reed-Sternberg Cells in Pediatric Patients With Classical Hodgkin Lymphoma. Pathol Oncol Res. 2022;28:1610482. doi: 10.3389/pore.2022.1610482.
  88. Baumforth KR, Birgersdotter A, Reynolds GM, et al. Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin’s lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells. Am J Pathol. 2008;173(1):195–204. doi: 10.2353/ajpath.2008.070845.
  89. Nagpal P, Descalzi-Montoya DB, Lodhi N. The circuitry of the tumor microenvironment in adult and pediatric Hodgkin lymphoma: cellular composition, cytokine profile, EBV, and exosomes. Cancer Rep (Hoboken). 2021;4(2):e1311. doi: 10.1002/cnr2.1311.
  90. Massini G, Siemer D, Hohaus S. EBV in Hodgkin Lymphoma. Mediterr J Hematol Infect Dis. 2009;1(2):e2009013. doi: 10.4084/MJHID.2009.013.
  91. Baumforth KR, Birgersdotter A, Reynolds GM, et al. Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin’s lymphoma cells mediates up-regulation of CCL20 and the migration of regulatory T cells. Am J Pathol. 2008;173(1):195–204. doi: 10.2353/ajpath.2008.070845.
  92. Pavlovic A, Glavina Durdov M, Capkun V, et al. Classical Hodgkin Lymphoma with Positive Epstein-Barr Virus Status is Associated with More FOXP3 Regulatory T Cells. Med Sci Monit. 2016;22:2340–6. doi: 10.12659/msm.896629.
  93. Steidl C, Connors JM, Gascoyne RD. Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol. 2011;29(14):1812–26. doi: 10.1200/JCO.2010.32.8401.
  94. Peh SC, Kim LH, Poppema S. TARC, a CC chemokine, is frequently expressed in classic Hodgkin’s lymphoma but not in NLP Hodgkin’s lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma. Am J Surg Pathol. 2001;25(7):925–9. doi: 10.1097/00000478-200107000-00011.
  95. Driessen J, Kersten MJ, Visser L, et al. Prognostic value of TARC and quantitative PET parameters in relapsed or refractory Hodgkin lymphoma patients treated with brentuximab vedotin and DHAP. Leukemia. 2022;36(12):2853–62. doi: 10.1038/s41375-022-01717-8.
  96. Kopinska A, Koclega A, Francuz T, et al. Serum thymus and activation-regulated chemokine (TARC) levels in newly diagnosed patients with Hodgkin lymphoma: a new promising and predictive tool? Preliminary report. J Hematopathol. 2021;14(4):277–81. doi: 10.1007/s12308-021-00470-8.
  97. Romano I, Puccini B, Signori L, et al. Serum TARC Concentration Kinetic in Classical Hodgkin Lymphoma during First-Line Treatment. Blood. 2021;138(Suppl 1):4500. doi: 10.1182/blood-2021-148137.
  98. Zijtregtop EAM, Tromp I, Dandis R, et al. The Prognostic Value of Eight Immunohistochemical Markers Expressed in the Tumor Microenvironment and on Hodgkin Reed-Sternberg Cells in Pediatric Patients With Classical Hodgkin Lymphoma. Pathol Oncol Res. 2022;28:1610482. doi: 10.3389/pore.2022.1610482.
  99. Vassilakopoulos TP, Nadali G, Angelopoulou MK, et al. Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin’s lymphoma. Haematologica. 2001;86(3):274–81.
  100. Aldinucci D, Borghese C, Casagrande N. Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It. Int J Mol Sci. 2019;20(10):2416. doi: 10.3390/ijms20102416.
  101. Menendez V, Solorzano JL, Fernandez S, et al. The Hodgkin Lymphoma Immune Microenvironment: Turning Bad News into Good. Cancers (Basel). 2022;14(5):1360. doi: 10.3390/cancers14051360.
  102. Ferrarini I, Rigo A, Visco C, et al. The Evolving Knowledge on T and NK Cells in Classic Hodgkin Lymphoma: Insights into Novel Subsets Populating the Immune Microenvironment. Cancers (Basel). 2020;12(12):3757. doi: 10.3390/cancers12123757.
  103. Vardhana S, Younes A. The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints. Haematologica. 2016;101(7):794–802. doi: 10.3324/haematol.2015.132761.
  104. Liu WR, Shipp MA. Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma. Blood. 2017;130(21):2265–70. doi: 10.1182/blood-2017-06-781989.
  105. Joller N, Kuchroo VK. Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol. 2017;410:127–56. doi: 10.1007/82_2017_62.
  106. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989–1004. doi: 10.1016/j.immuni.2016.05.001.
  107. Sakuishi K, Apetoh L, Sullivan JM, et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187–94. doi: 10.1084/jem.20100643.
  108. Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7–1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111–22. doi: 10.1016/j.immuni.2007.05.016.
  109. Patel SS, Weirather JL, Lipschitz M, et al. The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4-positive T cells that are PD-1-negative. Blood. 2019;134(23):2059–69. doi: 10.1182/blood.2019002206.
  110. Aoki T, Chong LC, Takata K, et al. Single-Cell transcriptome analysis reveals disease-defining T-cell subsets in the tumor microenvironment of classic Hodgkin lymphoma. Cancer Discov. 2019;10(3):406–21. doi: 10.1158/2159-8290.CD-19-0680.
  111. Gusak A, Fedorova L, Lepik K, et al. Immunosuppressive Microenvironment and Efficacy of PD-1 Inhibitors in Relapsed/Refractory Classic Hodgkin Lymphoma: Checkpoint Molecules Landscape and Macrophage Populations. Cancers. 2021;13(22):5676. doi: 10.3390/cancers13225676.
  112. Greaves P, Clear A, Owen A, et al. Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells. Blood. 2013;122(16):2856–63. doi: 10.1182/blood-2013-06-508044.
  113. Taylor JG, Truelove E, Clear A, et al. PDL1 shapes the classical Hodgkin lymphoma microenvironment without inducing T-cell exhaustion. Haematologica. 2023;108(4):1068–82. doi: 10.3324/haematol.2022.280014.
  114. Diefenbach CS, Hong F, Ambinder RF, et al. Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: phase 1 results of an open-label, multicentre, phase 1/2 trial. Lancet Haematol. 2020;7(9):e660–e670. doi: 10.1016/S2352-3026(20)30221-0.
  115. Wein F, Kuppers R. The role of T cells in the microenvironment of Hodgkin lymphoma. J Leukoc Biol. 2016;99(1):45–50. doi: 10.1189/jlb.3MR0315-136R.
  116. Aldinucci D, Gloghini A, Pinto A, et al. The role of CD40/CD40L and interferon regulatory factor 4 in Hodgkin lymphoma microenvironment. Leuk Lymphoma. 2012;53(2):195–201. doi: 10.3109/10428194.2011.605190.
  117. Veldman J, Visser L, Huberts-Kregel M, et al. Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58. Blood. 2020;136(21):2437–41. doi: 10.1182/blood.2020005546.
  118. Abdul Razak FR, Diepstra A, Visser L, van den Berg A. CD58 mutations are common in Hodgkin lymphoma cell lines and loss of CD58 expression in tumor cells occurs in Hodgkin lymphoma patients who relapse. Genes Immun. 2016;17(6):363–6. doi: 10.1038/gene.2016.30.
  119. Schneider M, Schneider S, Zuhlke-Jenisch R, et al. Alterations of the CD58 gene in classical Hodgkin lymphoma. Genes Chromosomes Cancer. 2015;54(10):638–45. doi: 10.1002/gcc.22276.
  120. Mulder TA, Andersson ML, Pena-Perez L, et al. Immune Biomarkers in the Peripheral Blood and Tumor Microenvironment of Classical Hodgkin Lymphoma Patients in Relation to Tumor Burden and Response to Treatment. Hemasphere. 2022;6(11):e794. doi: 10.1097/HS9.0000000000000794.
  121. Koenecke C, Ukena SN, Ganser A, Franzke A. Regulatory T cells as therapeutic target in Hodgkin’s lymphoma. Expert Opin Ther Targets. 2008;12(6):769–82. doi: 10.1517/14728222.12.6.769.
  122. Tanijiri T, Shimizu T, Uehira K, et al. Hodgkin’s Reed-Sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells. J Leukoc Biol. 2007;82(3):576–84. doi: 10.1189/jlb.0906565.
  123. Littringer K, Moresi C, Rakebrandt N, et al. Common Features of Regulatory T Cell Specialization During Th1 Responses. Front Immunol. 2018;9:1344. doi: 10.3389/fimmu.2018.01344.
  124. Marshall NA, Christie LE, Munro LR, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood. 2004;103(5):1755–62. doi: 10.1182/blood-2003-07-2594.
  125. Pan Y, Yu Y, Wang X, Zhang T. Tumor-Associated Macrophages in Tumor Immunity. Front Immunol. 2020;11:583084. doi: 10.3389/fimmu.2020.583084.
  126. Steidl C, Farinha P, Gascoyne RD. Macrophages predict treatment outcome in Hodgkin’s lymphoma. Haematologica. 2011;96(2):186–9. doi: 10.3324/haematol.2010.033316.
  127. Karihtala K, Leivonen SK, Bruck O, et al. Prognostic Impact of Tumor-Associated Macrophages on Survival Is Checkpoint Dependent in Classical Hodgkin Lymphoma. Cancers (Basel). 2020;12(4):877. doi: 10.3390/cancers12040877.
  128. Yao Y, Xu XH, Jin L. Macrophage Polarization in Physiological and Pathological Pregnancy. Front Immunol. 2019;10:792. doi: 10.3389/fimmu.2019.00792.
  129. Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233(9):6425–40. doi: 10.1002/jcp.26429.
  130. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: Tumor-Associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55. doi: 10.1016/s1471-4906(02)02302-5.
  131. Barros MHM, Segges P, Vera-Lozada G, et al. Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival. PLoS ONE 2015;10(5):e0124531. doi: 10.1371/journal.pone.0124531.
  132. Najafi M, Goradel NH, Farhood B, et al. Macrophage polarity in cancer: A review. J Cell Biochem. 2018;120(3):2756–65. doi: 10.1002/jcb.27646.
  133. Jiang Z, Sun H, Yu J, et al. Targeting CD47 for cancer immunotherapy. J Hematol Oncol. 2021;14(1):180. doi: 10.1186/s13045-021-01197-w.
  134. Li Z, Li Y, Gao J, et al. The role of CD47-SIRPα immune checkpoint in tumor immune evasion and innate immunotherapy. Life Sci. 2021;273:119150. doi: 10.1016/j.lfs.2021.119150.
  135. Oronsky B, Carter C, Reid T, et al. Just eat it: A review of CD47 and SIRP-α Semin Oncol. 2020;47(2–3):117–24. doi: 10.1053/j.seminoncol.2020.05.009.
  136. Gholiha AR, Hollander P, Lof L, et al. Checkpoint CD47 expression in classical Hodgkin lymphoma. Br J Haematol. 2022;197(5):580–9. doi: 10.1111/bjh.18137.
  137. Russ A, Hua AB, Montfort WR, et al. Blocking “don’t eat me” signal of CD47-SIRPα in hematological malignancies, an in-depth review. Blood Rev. 2018;32(6):480–9. doi: 10.1016/j.blre.2018.04.005.
  138. Hayat SMG, Bianconi V, Pirro M, et al. CD47: role in the immune system and application to cancer therapy. Cell Oncol (Dordr). 2020;43(1):19–30. doi: 10.1007/s13402-019-00469-5.
  139. Lu D, Ni Z, Liu X, et al. Beyond T Cells: Understanding the Role of PD-1/PD-L1 in Tumor-Associated Macrophages. J Immunol Res. 2019;2019:1919082. doi: 10.1155/2019/1919082.
  140. Vari F, Arpon D, Keane C, et al. Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood. 2018;131(16):1809–19. doi: 10.1182/blood-2017-07-796342.
  141. Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545(7655):495–9. doi: 10.1038/nature22396.
  142. Li W, Wu F, Zhao S, et al. Correlation between PD-1/PD-L1 expression and polarization in tumor-associated macrophages: A key player in tumor immunotherapy. Cytokine Growth Factor Rev. 2022;67:49–57. doi: 10.1016/j.cytogfr.2022.07.004.
  143. De la Cruz-Merino L, Lejeune M, Nogales Fernandez E, et al. Role of immune escape mechanisms in Hodgkin’s lymphoma development and progression: a whole new world with therapeutic implications. Clin Dev Immunol. 2012;2012:756353. doi: 10.1155/2012/756353.
  144. Calabretta E, d’Amore F, Carlo-Stella C. Immune and Inflammatory Cells of the Tumor Microenvironment Represent Novel Therapeutic Targets in Classical Hodgkin Lymphoma. Int J Mol Sci. 2019;20(21):5503. doi: 10.3390/ijms20215503.
  145. Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):3220–4. doi: 10.1182/blood-2007-05-085159.
  146. Xiong H, Mittman S, Rodriguez R, et al. Anti-PD-L1 Treatment Results in Functional Remodeling of the Macrophage Compartment. Cancer Res. 2019;79(7):1493–506. doi: 10.1158/0008-5472.CAN-18-3208.
  147. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71. doi: 10.1038/nature13954.
  148. Willenbrock K, Roers A, Blohbaum B, et al. CD8(+) T cells in Hodgkin’s disease tumor tissue are a polyclonal population with limited clonal expansion but little evidence of selection by antigen. Am J Pathol. 2000;157(1):171–5. doi: 10.1016/S0002-9440(10)64528-2.
  149. Neefjes J, Jongsma MLM, Paul P, et al. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011;11(12):823–36. doi: 10.1038/nri3084.
  150. Nagasaki J, Togashi Y, Sugawara T, et al. The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. Blood Adv. 2020;4(17):4069–82. doi: 10.1182/bloodadvances.2020002098.
  151. Cader FZ, Hu X, Goh WL, et al. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat Med. 2020;26(9):1468–79. doi: 10.1038/s41591-020-1006-1.
  152. Reinke S, Brockelmann PJ, Iaccarino I, et al. Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1. Blood. 2020;136(25):2851–63. doi: 10.1182/blood.2020008553.
  153. Brockelmann PJ, Goergen H, Keller U, et al. Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma: The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial. JAMA Oncol. 2020;6(6):872–80. doi: 10.1001/jamaoncol.2020.0750.
  154. Chen R, Zinzani PL, Lee HJ, et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood. 2019;134(14):1144–53. doi: 10.1182/blood.2019000324.
  155. Lepik KV, Fedorova LV, Kondakova EV, et al. A Phase 2 Study of Nivolumab Using a Fixed Dose of 40 mg (Nivo40) in Patients With Relapsed/Refractory Hodgkin Lymphoma. Hemasphere. 2020;4(5):e480. doi: 10.1097/HS9.0000000000000480.
  156. Herrera AF, Chen R, Palmer J, et al. PET-adapted nivolumab or nivolumab plus ICE as first salvage therapy in relapsed or refractory Hodgkin lymphoma. Blood. 2019;134(Suppl 1):239. doi: 10.1182/blood-2019-123162.
  157. Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma. Blood. 2021;137(10):1318–26. doi: 10.1182/blood.2020007400.
  158. Herrera AF, Burton C, Radford J, et al. Avelumab in relapsed/refractory classical Hodgkin lymphoma: phase 1b results from the JAVELIN Hodgkins trial. Blood Adv. 2021;5(17):3387–96. doi: 10.1182/bloodadvances.2021004511.
  159. Timmerman J, Lavie D, Johnson NA, et al. Favezelimab (anti–LAG-3) plus pembrolizumab in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 treatment: An open-label phase 1/2 study. J Clin Oncol. 2022;40(Suppl 16):7545. doi: 10.1200/JCO.2022.40.16_suppl.7545.
  160. Diefenbach CS, Hong F, Ambinder RF, et al. Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: phase 1 results of an open-label, multicentre, phase 1/2 trial. Lancet Haematol. 2020;7(9):e660–e670. doi: 10.1016/S2352-3026(20)30221-0.
  161. Fares CM, van Allen EM, Drake CG, et al. Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients? Am Soc Clin Oncol Educ Book. 2019;39:147–64. doi: 10.1200/EDBK_240837.
  162. Smaglo BG, Aldeghaither D, Weiner LM. The development of immunoconjugates for targeted cancer therapy. Nat Rev Clin Oncol. 2014;11(11):637–48. doi: 10.1038/nrclinonc.2014.159.
  163. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9. doi: 10.1200/JCO.2011.38.0410.
  164. Hamadani M, Collins GP, Samaniego F, et al. Phase 1 study of ADCT-301 (Camidanlumab Tesirine), a novel pyrrolobenzodiazepine-based antibody drug conjugate, in relapsed/refractory classical Hodgkin Lymphoma. Blood. 2018;132(Suppl 1):928. doi: 10.1182/blood-2018-99-118198.
  165. Flynn MJ, Hartley JA. The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer. Br J Haematol. 2017;179(1):20–35. doi: 10.1111/bjh.14770.
  166. Zelenay S, Lopes-Carvalho T, Caramalho I, et al. Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci USA. 2005;102(11):4091–6. doi: 10.1073/pnas.0408679102.
  167. Zinzani PL, Carlo-Stella C, Hamadani M, et al. Camidanlumab tesirine efficacy and safety in an open-label, multicenter, phase 2 study of patients (pts) with relapsed or refractory classical Hodgkin lymphoma (r/r cHL). Hematol Oncol. 2021;39(S2):125–7. doi: 10.1002/hon.75_2879.
  168. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–12. doi: 10.1158/0008-5472.CAN-05-4005.
  169. Smith CC, Perl AE, Lasater E, et al. PLX3397 Is An Investigational Selective FLT3 Inhibitor That Retains Activity Against the Clinically-Relevant FLT3-ITD/F691L “Gatekeeper” Mutation in Vitro. Blood. 2011;118(21):764. doi: 10.1182/blood.V118.21.764.764.
  170. Moskowitz CH, Younes A, de Vos S, et al. CSF1R Inhibition by PLX3397 in Patients with Relapsed or Refractory Hodgkin Lymphoma: Results From a Phase 2 Single Agent Clinical Trial. Blood. 2012;120(21):1638. doi: 10.1182/blood.V120.21.1638.1638.
  171. Fujiwara T, Yakoub MA, Chandler A, et al. CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. Mol Cancer Ther. 2021;20(8):1388–99. doi: 10.1158/1535-7163.MCT-20-0591.
  172. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022;387(24):2220–31. doi: 10.1056/NEJMoa2206913.
  173. Rothe A, Sasse S, Topp MS, et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(26):4024–31. doi: 10.1182/blood-2014-12-614636.
  174. Kerbauy LN, Marin ND, Kaplan M, et al. Combining AFM13, a Bispecific CD30/CD16 Antibody, with Cytokine-Activated Blood and Cord Blood-Derived NK Cells Facilitates CAR-like Responses Against CD30+ Malignancies. Clin Cancer Res. 2021;27(13):3744–56. doi: 10.1158/1078-0432.CCR-21-0164.
  175. Rajendran S, Li Y, Ngoh E, et al. Development of a Bispecific Antibody Targeting CD30 and CD137 on Hodgkin and Reed-Sternberg Cells. Front Oncol. 2019;9:945. doi: 10.3389/fonc.2019.00945.
  176. Piccione EC, Juarez S, Liu J, et al. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. MAbs. 2015;7(5):946–56. doi: 10.1080/19420862.2015.1062192.
  177. Wang Y, Ni H, Zhou S, et al. Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. Cancer Immunol Immunother. 2021;70(2):365–76. doi: 10.1007/s00262-020-02679-5.
  178. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294–308. doi: 10.1016/S0140-6736(22)00662-6.
  179. Ramos CA, Grover CA, Beaven AW, et al. Anti-CD30 CAR-T cell therapy in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2020;38(32):3794–804. doi: 10.1200/JCO.20.01342.
  180. Ruella M, Klichinsky M, Kenderian SS, et al. Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells. Cancer Discov. 2017;7(10):1154–67. doi: 10.1158/2159-8290.CD-16-0850.
  181. Shah SR, Tran TM. Lenalidomide in myelodysplastic syndrome and multiple myeloma. Drugs. 2007;67(13):1869–81. doi: 10.2165/00003495-200767130-00005.
  182. Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013;27(9):1902–9. doi: 10.1038/leu.2013.95.
  183. Fehniger TA, Larson S, Trinkaus K, et al. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011;118(19):5119–25. doi: 10.1182/blood-2011-07-362475.
  184. Kuruvilla J, Taylor D, Wang L, et al. Phase II trial of lenalidomide in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2008;112(11):3052. doi: 10.1182/blood.V112.11.3052.3052.
  185. Alonso-Alvarez S, Vidriales MB, Caballero MD, et al. The number of tumor infiltrating T-cell subsets in lymph nodes from patients with Hodgkin lymphoma is associated with the outcome after first line ABVD therapy. Leuk Lymphoma. 2017;58(5):1144–52. doi: 10.1080/10428194.2016.1239263.
  186. Zawati I, Adouni O, Manai M, et al. FOXP3+/CD68+ ratio within the tumor microenvironment may serve as a potential prognostic factor in classical Hodgkin lymphoma. Hum Immunol. 2022;83(12):843–56. doi: 10.1016/j.humimm.2022.08.013.
  187. Oudejans JJ, Jiwa NM, Kummer JA, et al. Activated cytotoxic T cells as prognostic marker in Hodgkin’s disease. Blood. 1997;89(4):1376–82.
  188. Alvaro T, Lejeune M, Salvado MT, et al. Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res. 2005;11(4):1467–73. doi: 10.1158/1078-0432.CCR-04-1869.
  189. Kelley TW, Pohlman B, Elson P, Hsi ED. The ratio of FOXP3+ regulatory T cells to granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression. Am J Clin Pathol. 2007;128(6):958–65. doi: 10.1309/NB3947K383DJ0LQ2.
  190. Schreck S, Friebel D, Buettner M, et al. Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma. Hematol Oncol. 2009;27(1):31–9. doi: 10.1002/hon.878.
  191. Agostinelli C, Gallamini A, Stracqualursi L, et al. The combined role of biomarkers and interim PET scan in prediction of treatment outcome in classical Hodgkin’s lymphoma: a retrospective, European, multicentre cohort study. Lancet Haematol. 2016;3(10):e467–e479. doi: 10.1016/S2352-3026(16)30108-9.
  192. Muenst S, Hoeller S, Dirnhofer S, Tzankov A. Increased programmed death-1+ tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival. Hum Pathol. 2009;40(12):1715–22. doi: 10.1016/j.humpath.2009.03.025.
  193. Nguyen TT, Frater JL, Klein J, et al. Expression of TIA1 and PAX5 in Classical Hodgkin Lymphoma at Initial Diagnosis May Predict Clinical Outcome. Appl Immunohistochem Mol Morphol. 2016;24(6):383–91. doi: 10.1097/PAI.0000000000000200.
  194. Chetaille B, Bertucci F, Finetti P, et al. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood. 2009;113(12):2765–3775. doi: 10.1182/blood-2008-07-168096.
  195. Greaves P, Clear A, Coutinho R, et al. Expression of FOXP3, CD68, and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma is predictive of outcome. J Clin Oncol. 2013;31(2):256–62. doi: 10.1200/JCO.2011.39.9881.
  196. Wang C, Xia B, Wang T, et al. PD-1, FOXP3, and CSF-1R expression in patients with Hodgkin lymphoma and their prognostic value. Int J Clin Exp Pathol. 2018;11(4):1923–34.
  197. Tzankov A, Meier C, Hirschmann P, et al. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008;93(2):193–200. doi: 10.3324/haematol.11702.
  198. Lacet DFR, Oliveira CC. The role of immunohistochemistry in the assessment of classical Hodgkin lymphoma microenvironment. Int J Clin Exp Pathol. 2022;15(10):412–24.
  199. Moerdler S, Ewart M, Friedman DL, et al. LAG-3 is expressed on a majority of tumor infiltrating lymphocytes in pediatric Hodgkin lymphoma. Leuk Lymphoma. 2021;62(3):606–13. doi: 10.1080/10428194.2020.1839651.
  200. Annibali O, Bianchi A, Grifoni A, et al. A novel scoring system for TIGIT expression in classic Hodgkin lymphoma. Sci Rep. 2021;11(1):7059. doi: 10.1038/s41598-021-86655-8.
  201. Karihtala K, Leivonen SK, Karjalainen-Lindsberg ML, et al. Checkpoint protein expression in the tumor microenvironment defines the outcome of classical Hodgkin lymphoma patients. Blood Adv. 2022;6(6):1919–31. doi: 10.1182/bloodadvances.2021006189.
  202. Guo B, Cen H, Tan X, Ke Q. Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med. 2016;14(1):159. doi: 10.1186/s12916-016-0711-6.
  203. Klein JL, Nguyen TT, Bien-Willner GA, et al. CD163 Immunohistochemistry is superior to CD68 in predicting outcome in classical Hodgkin lymphoma. Am J Clin Pathol. 2014;141(3):381–7. doi: 10.1309/AJCP61TLMXLSLJYS.
  204. Barros MHM, Hauck F, Dreyer JH, et al. Macrophage polarisation: An immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One. 2013;8(11):e80908. doi: 10.1371/journal.pone.0080908.
  205. Barros MH, Segges P, Vera-Lozada G, et al. Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival. PLoS One. 2015;10(5):e0124531. doi: 10.1371/journal.pone.0124531.
  206. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875–85. doi: 10.1056/NEJMoa0905680.
  207. Tudor CS, Distel LV, Eckhardt J, et al. B cells in classical Hodgkin lymphoma are important actors rather than bystanders in the local immune reaction. Hum Pathol. 2013;44(11):2475–86. doi: 10.1016/j.humpath.2013.06.006.
  208. Mizuno H, Nakayama T, Miyata Y, et al. Mast cells promote the growth of Hodgkin’s lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib. Leukemia. 2012;26(10):2269–76. doi: 10.1038/leu.2012.81.
  209. Glimelius I, Edstrom A, Fischer M, et al. Angiogenesis and mast cells in Hodgkin lymphoma. Leukemia. 2005;19(12):2360–2. doi: 10.1038/sj.leu.2403992.
  210. Ribatti D, Tamma R, Annese T, et al. Inflammatory microenvironment in classical Hodgkin’s lymphoma with special stress on mast cells. Front Oncol. 2022;12:964573. doi: 10.3389/fonc.2022.964573.
  211. Komi DEA, Redegeld FA. Role of Mast Cells in Shaping the Tumor Microenvironment. Clin Rev Allergy Immunol. 2020;58(3):313–25. doi: 10.1007/s12016-019-08753-w.
  212. Nakayama S, Yokote T, Hiraoka N, et al. Role of mast cells in fibrosis of classical Hodgkin lymphoma. Int J Immunopathol Pharmacol. 2016;29(4):603–11. doi: 10.1177/0394632016644447.
  213. Molin D, Fischer M, Xiang Z, et al. Mast cells express functional CD30 ligand and are the predominant CD30L-positive cells in Hodgkin’s disease. Br J Haematol. 2001;114(3):616–23. doi: 10.1046/j.1365-2141.2001.02977.x.
  214. Molin D, Edstrom A, Glimelius I, et al. Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol. 2002;119(1):122–4. doi: 10.1046/j.1365-2141.2002.03768.x.
  215. Keresztes K, Szollosi Z, Simon Z, et al. Retrospective analysis of the prognostic role of tissue eosinophil and mast cells in Hodgkin’s lymphoma. Pathol Oncol Res. 2007;13(3):237–42. doi: 10.1007/BF02893504.
  216. Andersen MD, Kamper P, Nielsen PS, et al. Tumour-associated mast cells in classical Hodgkin’s lymphoma: correlation with histological subtype, other tumour-infiltrating inflammatory cell subsets and outcome. Eur J Haematol. 2016;96(3):252–9. doi: 10.1111/ejh.12583.
  217. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th edition. Lyon: IARC Press; 2017.
  218. Von Wasielewski S, Franklin J, Fischer R, et al. Nodular sclerosing Hodgkin disease: new grading predicts prognosis in intermediate and advanced stages. Blood. 2003;101(10):4063–9. doi: 10.1182/blood-2002-05-1548.
  219. Pinto A, Aldinucci D, Gloghini A, et al. The role of eosinophils in the pathobiology of Hodgkin’s disease. Ann Oncol. 1997;8(Suppl 2):89–96.
  220. Enblad G, Sundstrom C, Glimelius B. Infiltration of eosinophils in Hodgkin’s disease involved lymph nodes predicts prognosis. Hematol Oncol. 1993;11(4):187–93. doi: 10.1002/hon.2900110404.
  221. Von Wasielewski R, Seth S, Franklin J, et al. Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin’s disease, allowing for known prognostic factors. Blood. 2000;95(4):1207–13.
  222. Konjevic G, Jurisic V, Jovic V, et al. Investigation of NK cell function and their modulation in different malignancies. Immunol Res. 2012;52(1–2):139–56. doi: 10.1007/s12026-012-8285-7.
  223. Chiu J, Ernst DM, Keating A. Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma. Front Immunol. 2018;9:267. doi: 10.3389/fimmu.2018.00267.
  224. Reiners KS, Kessler J, Sauer M, et al. Rescue of impaired NK cell activity in Hodgkin lymphoma with bispecific antibodies in vitro and in patients. Mol Ther. 2013;21(4):895–903. doi: 10.1038/mt.2013.14.
  225. Tursz T, Dokhelar MC, Lipinski M, Amiel JL. Low natural killer cell activity in patients with malignant lymphoma. Cancer. 1982;50(11):2333–5. doi: 10.1002/1097-0142(19821201)50:11<2333::aid-cncr2820501119>3.0.co;2-w.
  226. Alvaro-Naranjo T, Lejeune M, Salvado-Usach MT, et al. Tumor-infiltrating cells as a prognostic factor in Hodgkin’s lymphoma: a quantitative tissue microarray study in a large retrospective cohort of 267 patients. Leuk Lymphoma. 2005;46(11):1581–91. doi: 10.1080/10428190500220654.
  227. Zanna MY, Yasmin AR, Omar AR, et al. Review of Dendritic Cells, Their Role in Clinical Immunology, and Distribution in Various Animal Species. Int J Mol Sci. 2021;22(15):8044. doi: 10.3390/ijms22158044.
  228. Galati D, Zanotta S, Corazzelli G, et al. Circulating dendritic cells deficiencies as a new biomarker in classical Hodgkin lymphoma. Br J Haematol. 2019;184(4):594–604. doi: 10.1111/bjh.15676.
  229. Tudor CS, Bruns H, Daniel C, et al. Macrophages and dendritic cells as actors in the immune reaction of classical Hodgkin lymphoma. PLoS One. 2014;9(12):e114345. doi: 10.1371/journal.pone.0114345.
  230. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485–98. doi: 10.1038/s41577-020-00490-y.
  231. Romano A, Parrinello NL, Vetro C, et al. Circulating myeloid-derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up-front with a risk-adapted strategy. Br J Haematol. 2015;168(5):689–700. doi: 10.1111/bjh.13198.
  232. Novosad O, Gorbach O, Skachkova O, et al. Role of Circulating Myeloid-Derived Suppressor Cell (MDSC) in Hodgkin Lymphoma (HL) Progression: Updated Prospective Study. Blood. 2020;136(Suppl 1):31. doi: 10.1182/blood-2020-141259.
  233. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31–46. doi: 10.1158/2159-8290.CD-21-1059.
  234. Korkolopoulou P, Thymara I, Kavantzas N, et al. Angiogenesis in Hodgkin’s lymphoma: a morphometric approach in 286 patients with prognostic implications. Leukemia. 2005;19(6):894–900. doi: 10.1038/sj.leu.2403690.
  235. Karihtala K, Leivonen SK, Karjalainen-Lindsberg ML, et al. T026: Characterization of cancer-associated fibroblasts in classical Hodgkin lymphoma. Hemasphere. 2022;6(Suppl):13. doi: 10.1097/01.HS9.0000890672.81592.33.
  236. Bankov K, Doring C, Ustaszewski A, et al. Fibroblasts in Nodular Sclerosing Classical Hodgkin Lymphoma Are Defined by a Specific Phenotype and Protect Tumor Cells from Brentuximab-Vedotin Induced Injury. Cancers (Basel). 2019;11(11):1687. doi: 10.3390/cancers11111687.
  237. Kamper P, Bendix K, Hamilton-Dutoit S, et al. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica. 2011;96(2):269–76. doi: 10.3324/haematol.2010.031542.
  238. Tan KL, Scott DW, Hong F, et al. Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood. 2012;120(16):3280–7. doi: 10.1182/blood-2012-04-421057.
  239. Azambuja D, Natkunam Y, Biasoli I, et al. Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin’s lymphoma. Ann Oncol. 2012;23(3):736–42. doi: 10.1093/annonc/mdr157.
  240. Werner L, Dreyer JH, Hartmann D, et al. Tumor-associated macrophages in classical Hodgkin lymphoma: hormetic relationship to outcome. Sci Rep. 2020;10(1):9410. doi: 10.1038/s41598-020-66010-z.
  241. Panico L, Ronconi F, Lepore M, et al. Prognostic role of tumor-associated macrophages and angiogenesis in classical Hodgkin lymphoma. Leuk Lymphoma. 2013;54(11):2418–25. doi: 10.3109/10428194.2013.778405.
  242. Ng WL, Ansell SM, Mondello P. Insights into the tumor microenvironment of B cell lymphoma. J Exp Clin Cancer Res. 2022;41(1):362. doi: 10.1186/s13046-022-02579-9.
  243. Chen X, Cho DB, Yang PC. Double staining immunohistochemistry. N Am J Med Sci. 2010;2(5):241–5. doi: 10.4297/najms.2010.2241.
  244. Parra ER, Uraoka N, Jiang M, et al. Validation of multiplex immunofluorescence panels using multispectral microscopy for immune-profiling of formalin-fixed and paraffin-embedded human tumor tissues. Sci Rep. 2017;7(1):13380. doi: 10.1038/s41598-017-13942-8.
  245. Ijsselsteijn ME, van der Breggen R, Farina Sarasqueta A, et al. A 40-Marker Panel for High Dimensional Characterization of Cancer Immune Microenvironments by Imaging Mass Cytometry. Front Immunol. 2019;10:2534. doi: 10.3389/fimmu.2019.02534.
  246. Marx V. Method of the Year: spatially resolved transcriptomics. Nat Methods. 2021;18:9–14. doi: 10.1038/s41592-020-01033-y.
  247. Lee MKI, Rabindranath M, Faust K, et al. Compound computer vision workflow for efficient and automated immunohistochemical analysis of whole slide images. J Clin Pathol. 2022:jclinpath-2021-208020. doi: 10.1136/jclinpath-2021-208020.
  248. Wilson CM, Ospina OE, Townsend MK, et al. Challenges and Opportunities in the Statistical Analysis of Multiplex Immunofluorescence Data. Cancers (Basel). 2021;13(12):3031. doi: 10.3390/cancers13123031.
  249. M’kacher R, Frenzel M, Al Jawhari M, et al. Establishment and Characterization of a Reliable Xenograft Model of Hodgkin Lymphoma Suitable for the Study of Tumor Origin and the Design of New Therapies. Cancers (Basel). 2018;10(11):414. doi: 10.3390/cancers10110414.
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